Foreword by Robert A. Harrington xiii Preface xv List of Abbreviations xviii 1 Lessons from a Horse Named Jim and Other Events in History Affecting the Regulation of Clinical Research 1 2 The Process: Developing New Drugs, Biologics, and Devices 13 The Drug Development Process 14 Background Information 14 Pre-Clinical Studies 15 The Investigational New Drug Application 16 Clinical Trial Phases 17 Application to Market New Drugs and Biologics 20 FDA Review Groups 21 Early or Expanded Access to Unapproved Drugs and Biologics 24 Orphan Drugs 25 Developing New Devices 26 Background Information 27 What is a Medical Device? 28 Medical Device Classification 29 Requirements for Marketing New Devices 33 Humanitarian Use Devices 36 Early or Expanded Access to Unapproved Medical Devices 36 FDA Device Review 38 Combination Products 38 Postmarketing Surveillance of Drugs, Biologics, and Devices 39 Phase 4 Postmarketing Drug and Biologics Studies 40 Phase 4 Postmarketing Device Studies 40 Direct Reporting Based on Observations 41 3 Good Clinical Practice and the Regulations 49 Good Clinical Practice 50 Regulations 50 Guidelines 59 Local Laws 60 Responsibilities in the Code of Federal Regulations 62 Principal Investigator Responsibilities 62 Institutional Review Board Responsibilities 67 Sponsor Responsibilities 68 Sponsor-Investigators 70 Where to Obtain Information and Guidance for the Regulations and GCP 70 The Federal Register 70 FDA Guidance Documents 71 Online Resources 71 4 Informed Consent and the Regulations 73 What Is Informed Consent? 74 Ethical Codes Regarding Informed Consent 75 The Belmont Report: Application of Respect for Persons 75 The Declaration of Helsinki 76 The Nuremberg Code 77 Regulatory Requirements for Informed Consent 77 General Requirements for Informed Consent (21 CFR 50.20) 78 Exceptions from the General Requirements (21 CFR 50.23) 79 Exceptions from Informed Consent Requirements for Emergency Research (21 CFR 50.24) 79 Elements of Informed Consent (21 CFR 50.25) 80 Documentation of Informed Consent (21 CFR 50.27) 82 Consent from Vulnerable Subjects 85 HIPAA/Privacy Rule Requirements 90 The Informed Consent Process 92 Writing the Consent Form 92 Obtaining Informed Consent 95 Documenting Informed Consent 96 Continuing Informed Consent 97 5 Institutional Review Boards 101 What is an Institutional Review Board? 102 Types of IRBs 103 IRB Membership 104 IRB Activities 107 Reviewing Research 107 Reporting Unanticipated Problems Involving Risks to Subjects or Others 109 Establishing Written Procedures 110 Types of IRB Review 111 Full Committee Review 111 Expedited Review 112 Items That Must be Submitted for IRB Review 113 Exemptions: When IRB Approval Is Not Required 113 Continuing Review after Initial Study Approval 114 Review of Adverse Events and Unanticipated Problems 115 Communication between IRBs and Investigators 116 Investigator Notification of the Outcome of IRB Review 116 Communication During Study 116 IRB Notification at Study Completion 117 Communication between IRBs and Study Sponsors 117 IRB Records and Reports 118 Accreditation of IRBs 119 Registration 120 6 Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others 123 Why Collect Adverse Event Data? 124 Safety Profile 125 Benefits and Risks Evaluation 125 Package Insert 125 Adverse Events 125 Internal and External Adverse Events 126 Serious Adverse Events 126 Unanticipated Problems Involving Risks to Subjects or Others 127 Investigator Responsibilities 129 Collecting Adverse Event Data 129 Reporting Adverse Event Data 130 Expedited Reporting of Adverse Events 131 Reporting Unanticipated Problems Involving Risks to Subjects or Others 133 Reporting Unanticipated Adverse Device Effects 135 IRB Responsibilities 135 Review and Reporting of Serious Adverse Events 135 Review and Reporting of Unanticipated Problems 136 Sponsor Responsibilities 136 Expedited Reporting in Drug Trials 137 Expedited Reporting in Device Trials 138 Routine Reporting by Sponsors 139 7 Monitoring, Audits, and Inspections 141 Monitoring Plan 143 On-Site Monitoring 144 Types of On-Site Monitoring Visits 145 Documenting Monitoring Visits 151 In-House Monitoring 152 Computerized Checks 153 Source Document Verification Done at the Sponsor or Data Center 153 Protected Health Information 154 Audits and Inspections 154 Audits and Inspections in the Regulations and Guidelines 155 Sponsor Quality Assurance Audits 156 FDA Inspections 157 8 The Principal Investigator, the Clinical Research Coordinator, and the Study Site 163 The Principal Investigator 164 Characteristics of an Effective Principal Investigator 165 Conflict of Interest 167 Investigator Delegation of Study Activities 169 Staffing to Support Clinical Trials 169 Clinical Research Coordinator 169 Subinvestigators 172 Support Personnel 173 Space and Resource Needs 173 Workspace for the Clinical Research Coordinator 173 Equipment 174 Storage Space 174 Additional Space 175 The Local Institutional Review Board 175 9 The Protocol 177 Common Components of a Protocol 180 Background and Rationale 180 Study Organization 180 Objectives/Endpoints 181 Quality of Life Parameters 181 Economic Factors 182 Surrogate Endpoints 182 Study Design 183 Use of Control Groups 184 Randomization 185 Blinding 187 Observational Studies 188 Study Population 190 Study Treatment Plan 191 Safety Assessment, Management, and Reporting 192 Replacement of Withdrawn, Dropped Out, and Lost to Follow-up Subjects 193 Statistical Aspects 193 Power 193 Sample Size 193 Intention-to-treat Principle 194 Interim Analysis 195 Data and Safety Monitoring Board 196 Subject Data and Record Retention 197 Monitoring 197 10 Study Feasibility: Reviewing a Specific Protocol 199 Reviewing a Specific Protocol 200 Study Design 200 Research Subject Population 201 Investigator Time Requirements 202 Clinical Research Coordinator and Other Study Personnel 202 Laboratory Tests and Procedures 204 Additional Space and Equipment 205 Budget Considerations 206 Preparing a Budget 207 Budget Planning 209 Negotiating a Budget 211 Should We Do this Study at Our Site? 211 11 Study Activities 213 Study Start-up Phase 215 Review the Protocol, Develop a Budget, Prepare Documents for IRB Submission 215 Establish the Site Study Team 216 Participate in Investigator Meetings 219 Develop a Recruitment and Enrollment Plan 219 Conduct Education and Training Sessions for Site Personnel 228 Begin Randomization and Enrollment of Subjects 230 Study Maintenance Phase 230 Complete Data Forms 231 Report Serious Adverse Events (SAE) and Unanticipated Problems 231 Conduct Subject Follow-up Visits 231 Ensure Subject Retention and Compliance 233 Unblind Study Treatment Only When Required 238 Maintain Study Drug/Device Accountability 239 Manage Specimens, Samples, and Other Study-related Materials 239 Obtain Answers to Urgent Clinical Questions 239 Continue Communication 239 Maintain Study File 240 Study Completion and Close-Out Phase 240 Completion of All Subject Data Forms and Resolution of Data Queries 241 Destruction or Return of Study Materials 241 Review of Site Study File 241 Submission of the Final Report 241 Long-term Storage of Study Records 242 12 Study Documents/Essential Documents 245 Documents at Study Start-Up 246 Confidentiality Agreement 247 Signed Protocol and Applicable Amendments 247 Letter of Agreement 247 Investigator''s Brochure 248 Curriculum Vitae (CV)/Statement of Investigator Qualifications 248 Medical Licensure Form 248 Form FDA 1572 248 Financial Disclosure Information 250 IRB Approval 250 IRB-Approved Consent Form 252 RB-Approved Advertisements and Subject Materials 253 Laboratory Certification and Normal Ranges Form 253 Site Demographics Form 255 Study Personnel CVs/Résumés and Training Records 255 Contractual Agreement/Financial Contract 255 Documents While the Study is in Progress 256 Protocol Amendments and IRB Approval 256 Revised Consent Forms and IRB Approval 257 Updated Form FDA 1572 257 CVs for New PIs and Subinvestigators 257 Updated Laboratory Certification and Normal Ranges Form 258 IRB Correspondence 258 Subject Recruitment Advertisements and Educational Materials 258 Screening Log 258 Confidential Master Subject Log 259 Signed Consent Forms for All Enrolled Subjects 259 Test Article Accountability Forms 259 <.